Oligometastatic Prostate Cancer: Is there a Role for Surgery? A Narrative Review

Oligometastatic prostate cancer is commonly considered a transition between high metastatic and localized disease and includes a large spectrum of conditions with a polymorphic clinical behavior. The current management of these patients contemplates systemic therapy (i.e., androgen-deprivation drugs, chemotherapeutic drugs, or both treatments administered simultaneously) which have been shown to improve survival. Radiotherapy has also been introduced, into a multimodal setting, among the therapeutic treatments for patients who are defined as oligometastatic prostate cancer according to Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) criteria. The role of surgical debulking in patients with oligometastatic prostate cancer has always been considered impracticable, both for a marginal therapeutic role and for the greater risk of sequelae and/or complications related to the procedure itself. Several authors have demonstrated some mechanisms by which the persistence of the primary tumor can facilitate the clinical progression of the disease itself and promote carcinogenesis, differentiation, migration, and angiogenesis in prostate cancer. From these studies emerges the hypothesis of a possible therapeutic advantage in oncological terms also for cytoreductive radical prostatectomy, in a multimodal therapy setting, compared to systemic therapy alone. The present review summarizes the main knowledge regarding the safety, feasibility, and oncological outcomes of cytoreductive radical prostatectomy in oligometastatic prostate cancer patients.


Introduction
Prostate cancer is the second most widespread cancer diagnosed in the United States, the third for cancer death with about 248 530 new cases and about 34 130 deaths in 2021. 1 In 2018, about 20% of the 1.3 million worldwide with PCa diagnosed had metastatic disease. 2 Oligometastatic prostate cancer (OMPC) is commonly defined by the presence of 5 or fewer metastatic sites on usual staging imaging. It is considered a transition between high metastatic and organ-confined disease and includes a large spectrum of conditions with a polymorphic clinical behavior. 3 The current management of these patients contemplates systemic therapy (i.e., androgendeprivation drugs, chemotherapeutic drugs, or both treatments administered simultaneously) which have been shown to improve survival. Radiotherapy has also been introduced, into a multimodal setting, among the therapeutic treatments of patients defined as OMPC according to CHAARTED criteria. 4 The role of surgical debulking in patients with OMPC has always been considered impracticable, both for a marginal therapeutic role and for the greater risk of sequelae and/or complications related to the procedure itself.
Several authors have demonstrated some mechanisms by which the persistence of the primary tumor can facilitate the clinical progression of the disease itself. Vassiliki et al 5  of primary tumor may promote metastatic disease spread by altering the translation and regulation pathways of cellular signal. This results in cell proliferation, de-differentiation, cancer lymphatic and/or hematogenous dissemination, and angiogenesis.
Cifuentes et al 7 first reported how surgical debulking of resectable PCas limits metastatic progression in a mouse model.
From these studies emerges the hypothesis of a possible therapeutic advantage in oncological terms also for cytoreductive radical prostatectomy (CRP), in a multimodal therapy setting, in patients with OMPC compared to systemic therapy alone.

Definition End Prevalence of OMPC
No consensus exists to identify the OMPC. Actually, it is commonly defined by the presence of 5 or fewer metastatic sites on usual staging imaging The prevalence of OMPC varies significantly in the literature. It strongly depends on the imaging examinations adopted to stage the disease.
Same authors demonstrated a restaging of a cohort of patients initially diagnosed as locally confined PCa as OMPC patients by using higher sensitive imaging examinations such as 18-F-fluciclovine positron emission tomography (PET) scan. Likewise, patients diagnosed initially with OMPC were restaged as high volume metastatic disease using more sensitive imaging techniques. 8 From this evidence emerges the need to make some considerations to frame the disease in a correct clinical and biological context, even before evaluating the feasibility of CRP in terms of safety and oncological results. First, the disease should be distinguished from the more aggressive one early diagnosed with a high polymetastatic potential. Biologically, OMPC should be considered a slow-growing and low-metastatic power disease. Support for this definition comes from the TROG 03.04 Randomised Androgen Deprivation and Radiotherapy (RADAR) trial (a phase III randomized study that compared 6 vs. 18 months of adjuvant ADT with or without zoledronic acid in men with intermediate/high-risk PCa undergoing radiotherapy (RT)). The study confirmed that patients with 4 or more metastasis had significantly higher PCa-specific mortality than those with oligometastatic disease (P = .004). 9 Also, a distinction between de novo oligometastatic and recurrent oligometastatic disease should be made since their biological and clinical behavior is different.

Safety, Feasibility, and Quality of Life of CRP in OMPC Patients
There seems to be a consensus on the safety and the feasibility of CRP in OMPC patients and this evidence should encourage further investigation on surgical treatment ( Table 1 summarizes this evidence).
Heidenreich et al 10 in a case-control study investigated the feasibility of CRP in patient with OMPC. No differences were reported in terms of frequency and seriousness of surgeryrelated complications in OMPC patients compared to high-risk non-metastatic PCa patients.
Sooriakumaran et al 11 in a multi-institutional analysis examined the safety of CRP in 106 patients with OMPC. No complication were experienced in 79.2% of patients. Positive-margin (53.8%), lymphocele (8.5%), and wound infection (4.7%) rates were higher than in surgery performed for locally confined disease. At 22.8 months follow-up, 88.7% of men were still alive. They concluded that surgery is safe in expert hands and that the overall and specific complication rates related to CRP were not higher than surgical treatment of locally confined PCa.
Conversely, Gandaglia et al 12 in a single-center study, enrolling 11 patients, reported 20% of Clavien-Dindo grade-III complications, a significant increase in intraoperative blood loss requiring transfusion, and an increase in post-operative hospitalization compared to those undergoing surgical treatment for localized disease. They concluded that CRP has a tolerable safety profile and it is technically more challenging.

Main Points
• Oligometastatic prostate cancer is considered a transition between high metastatic and localized disease and includes a large spectrum of conditions with a polymorphic clinical behavior.
• Some cell signals of primary tumor can facilitate the disease progression by promoting carcinogenesis, differentiation, migration, and angiogenesis.
• Cytoreductive radical prostatectomy (CRP) is safe, feasible, and well-tolerated in a well-selected group of patients and, despite its challenging execution, it is associated with a reduction of pelvic complications related to local disease progression.
• Oligometastatic prostate cancer patients may receive deep and durable oncological benefits from CRP within a multimodality setting. Global health status worsened significantly in localized disease patients compared to baseline (P = .001), whereas it did not change significantly in oligometastatic patients (P = .381). They concluded that there is no significant difference in HRQOL in OMPC patient after CRP, when compared to patients with organ-confined disease at the time of surgery.

Oncological Outcomes of CRP in OMPC Patients
Looking at other metastatic diseases, there are deep evidence showing the benefit of cytoreductive surgery in terms of patient survival. 15 In contrast, the role of CRP has not been rigorously evaluated.
There are no studies able to answer this question, but prospective trials are ongoing [TRoMbone trial, 16 SWOG S1802 randomized phase III trial, 17 G-RAMMP phase III trial. 18 Although the evidence is limited, there are some retrospective data suggesting a potential role for CRP in OMPC ( Table 2 summarizes these data).
To our knowledge, Austenfeld et al. 19 in 1990, first reported significant benefits of CRP in well-selected OMPC patients in terms of progression rates or disease-free survival.
In a population-based study using the Munich Cancer Registry, Engel et al 20 compared the overall mortality (OM) and relative survival of OMPC patients undergoing CRP (n = 688) and in patients who have not received local treatment (n = 250). An improvement in 10-year OM (64% vs. 28%) and relative survival (86% vs. 40%) was reported in the CRP group. Moreover, on multivariate analysis, CRP was an independent predictor of increased survival (P < .0001).
• CRP (P < .01) and IMRT (P < .01) were independently associated with higher overall survival. After PS-matching, the use of LT remained significantly associated with overall survival (P < .01).

Conclusions
Oligometastatic prostate cancer is a transitional disease including a large spectrum of conditions with a polymorphic behavior and the correct diagnosis of OMPC requires more sensitive imaging techniques.
Cytoreductive radical prostatectomy is safe, feasible, and welltolerated in a well-selected group of patients and, despite its challenging execution, it is associated with reduction of pelvic complications related to local disease progression.
Treatment options are rapidly evolving and, waiting for the results of ongoing prospective-multicentric and randomized trials, a growing body of evidence suggests that a group of OMPC patients may receive deep and durable oncological benefits from CRP within a multimodality setting.

Statement of human rights
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Declaration of Interests:
The authors have no conflict of interest to declare.

Funding:
The authors declared that this study has received no financial support.